The Suzuki-Miyaura reaction is a palladium- or nickel-catalyzed cross coupling between a boronic acid or a boronic ester and an organohalide or an organo-pseudohalide. Miyaura, A. Chem. Rev., 1995. This cross coupling transformation is a powerful method for C—C bond formation in complex molecule synthesis. The reaction is tolerant of functional groups and has become increasingly general and widespread in its use for coupling of organic compounds. Barder, T. E. et al., J. Am. Chem. Soc. 2005, 127, 4685-4696; Billingsley, K. et al., J. Am. Chem. Soc. 2007, 129, 3358-3366; Littke, A. F. et al., J. Am. Chem. Soc. 2000, 122, 4020-4028; Nicolaou, K. C. et al., Angew. Chem. Int. Ed. 2005, 44, 4442-4489.
Boronic acids are notoriously sensitive to many common reagents. Hall, D. G., Boronic Acids, Wiley-VCH, Germany, 2005, pp. 3-14; Tyrell, E. et al., Synthesis 2003, 4, 469-483. It is therefore typical to introduce the boronic acid functional group during the last step of a building block synthesis. However, many of the methods for doing so (hydroboration, trapping organometallic reagents with trimethylborate, etc.) are intolerant to a variety of common functional groups, such as alcohols, aldehydes, ketones, alkynes and olefins. This makes the synthesis of structurally complex boronic acid building blocks quite challenging.
Peptides, oligonucleotides, and increasingly oligosaccharides can be rapidly and flexibly prepared in the laboratory from readily accessible building blocks having all of the required site- and stereochemical information pre-installed.1 The inherent modularity of many small molecules and the rapidly expanding scope of boronic acid cross-coupling chemistry2-4 collectively support the notion that an analogous building block-based approach for small molecule synthesis may be attainable.5 However, at present, unactivated Csp3 organoboronates cannot be cross-coupled with the same levels of efficiency, site-, and stereo-retention that is now accessible with many of their Csp2 and activated Csp3 hybridized counterparts.2-4 Solving this problem stands to enable a wide range of stereochemically complex natural products and Csp3-rich pharmaceuticals7 to be more efficiently and flexibly prepared via the simple site- and stereo-retentive assembly of off-
U.S. Pat. No. 8,013,203 (incorporated by reference), U.S. Pat. No. 8,318,983 (incorporated by reference), and US 2013/0296573 (incorporated by reference), each to Burke et al., disclose protected organoboronic acid compounds comprising a boron having an sp3 hybridization, a conformationally rigid protecting group bonded to the boron, and an organic group bonded to the boron through a boron-carbon bond; methods of making same; and methods of performing chemical reactions using same. In an embodiment, the protected organoboronic acid is an N-methyliminodiacetic acid (MIDA) boronate.
U.S. Pat. No. 8,338,601 (incorporated by reference) and US 2013/0317223 (incorporated by reference), each to Burke et al., disclose methods of performing chemical reactions using protected organoboronic acid compounds. In an embodiment, the protected organoboronic acid is a MIDA boronate. In an embodiment, the reaction is a cross-coupling reaction.
U.S. Pat. No. 8,557,980 (incorporated by reference) and US 2014/0073785 (incorporated by reference), each to Burke et al., disclose methods of forming protected boronic acids that provide a wide variety of building blocks for use in chemical reactions. In an embodiment, the protected boronic acid is a MIDA boronate. In an embodiment, the reaction is a cross-coupling reaction.
US 2013/0243670 (incorporated by reference) to Burke et al. discloses methods and an apparatus for purification of MIDA boronates and deprotection of boronic acids from their MIDA ligands to perform cross-coupling reactions. Iterative cycles of deprotection, coupling, and purification can be used to synthesize small molecules.
US 2014/0094615 (incorporated by reference) to Burke et al. discloses methods of making and using chiral, non-racemic protected organoboronic acid compounds to direct and enable stereoselective synthesis of organic molecules. In an embodiment, the chiral, non-racemic protected organoboronic acid compounds are chiral derivatives of iminodiacetic acid (IDA).